Summary of the context and overall objectives of the project

Worldwide, populations are aging progressively, which goes along with a burden of age-associated diseases that have a strong personal and economic impact on those affected, but also on society as a whole. Although reduced caloric intake and increased exercise improve health, Western societies are dominated by fat-enriched diets and lack of exercise. Therefore, caloric restriction and exercise mimetics have been developed that reproduce the benefits under population-wide realistic caloric intake or exercise efforts. The identification of a novel anti-aging pathway will not only give more insight in the basic biology of aging, but also open new avenues for targeting age-related diseases.

Aging has long been considered a passive process. More recently studies have defined an important, active role for metabolic pathways in aging and age-related diseases. We have previously demonstrated a marked dysregulation of fat metabolism in aged mice that contributes to their overweight and glucose intolerance. The MetaFlex model links healthy aging to efficient processing of nutrients, a state termed metabolic flexibility: reducing protein or carbohydrate metabolism will strongly stimulate fat breakdown. We suggest that improved metabolic flexibility will prevent the accumulation of lipids and protect against its detrimental effects.

The main goal of this project will be to further clarify the interplay of nutrient sensing, metabolism and aging. Specific aims are:

1) To elucidate the role of nutrient breakdown pathways in aging. 2) To clarify the mechanisms by which metabolic flexibility prevents aging.

On the long term, my research group aims to better understand the metabolic changes that occur in the aging individual, how these changes affect the aging process, and if they can be targeted to promote healthy aging.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

To establish the metabolic changes in aging worms, we performed extensive profiling of C. elegans during different stages of their life, and found marked differences in amino acids and fats, suggesting that these contribute to the aging process. As a follow up, we developed various types of diets that could confirm these hypotheses. We are exposing the worms to these diets and assess the impact on the metabolic health and lifespan. We found that specific fat diets shorten lifespan and are in the process of elucidating the mechanisms. Using worms that lack certain metabolic flexibility genes, we established that these genes are critical for the age-dependent changes in metabolism.

A second focus is which genes can explain the response to these diets. In a preliminary screen, we identified one gene in particular that, when silenced, attenuates the harmful effects of the diets. We further defined the health benefits and life extension caused by silencing the gene in C. elegens. Finally, we are working on elucidating the gene networks that integrate metabolic and nutritional cues. We are using gene expression arrays to identify the signatures of longevity in worms with altered metabolic profiles. In addition to that we are setting up population-type studies in C. elegans that allow us to detect how subtle variations in genetic composition affect the response to dietary intervention. In other words, why do some worms show premature aging when exposed to a diet, while others do not.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

Scientific impact:As our research is at the forefront of the metabolic aging field, we are continuously improving the state-of-the-art technologies that are required to answer our research questions. For instance, we developed several platforms for the measurement of metabolites and metabolic fluxes in C. elegans. These methods are getting increasingly popular and we receive many requests for collaboration.

Societal impact:-Considering that we primarily work with the worm C. elegans, there is still a long way to application in humans. Nevertheless, we are seeking opportunities for translation of our findings as many of the concepts can be applied to other fields of research as well. For instance, we are collaborating with leaders in the field of immunometabolism who apply our concepts of metabolic flexibility to their cell system.-We are seeking outreach opportunities to enlighten the general public but also policy makers about blue sky research. For instance, my research was featured in the ERC-supported Science Squared campaign “The Taste Tests”, http://www.sciencesquared.eu/taste-tests, and I participated as a speaker at the meeting “Research Strategies: Europe 2030 and the next Framework Programme” (http://sciencebusiness.net/events/2016/research-strategies-europe-2030-and-the-next-framework-programme/).